Oxanorbornadiene Explained

Oxanorbornadiene (OND) is a bicyclic organic compound with an oxygen atom bridging the two opposing saturated carbons of 1,4-cyclohexadiene. OND is related to all-carbon bicycle norbornadiene.

Synthesis

While unsubstituted OND is known, the most useful OND derivatives are dialkyl OND-2,3-dicarboxylates, readily obtainable by a Diels–Alder cycloaddition between furans and acetylenedicarboxylates such as DMAD.[1]

Properties

OND-2,3-dicarboxylates (thereafter referred to as OND) display unusually high reactivity towards organic azides[2] and thiols.[3] OND–thiol adducts are prone to retro-Diels–Alder fragmentation, which occurs with widely variable rates.[4]

Reactions with azides

ONDs react with organic azides to yield a mixture of four products, arising from initial 1,3-dipolar cycloaddition onto either of the two olefins, followed by a retro-Diels–Alder reaction (a cycloelimination reaction) to form 1,2,3-triazoles and furans. The intermediate triazolines avoid detection because of a very strong thermodynamic drive to collapse into two aromatic products. The relative preference of attack on either double bond is governed by the electronic nature of the azides. Electron-rich aliphatic azides, e.g. benzyl azide, react preferentially via their HOMO orbital. Interaction of the azide HOMO with LUMO orbital of the OND, localized on the electron-poor C-2 and C-3, leads the products consistent with path A. Electron-poor aryl azides, such as p-nitrophenyl azide, react, to a significant extent, via their LUMO orbitals, interacting with OND HOMO (C-5 and C-6), leading to higher amounts of path B products. The dipolar reactivity of OND with azides is unusually high for olefins, and even exceeds that of parent electron-poor alkyne DMAD.[4] [5]

Notes and References

  1. 10.1002/jlac.19314900110. Synthesen in der hydroaromatischen Reihe. XII. Mitteilung. („Dien-Synthesen” sauerstoffhaltiger Heteroringe. 2. Dien-Synthesen des Furans.). 1931. Diels. Otto. Alder. Kurt. Justus Liebig's Annalen der Chemie. 490. 1. 243–257.
  2. 10.1002/cbic.200700278. Metal-Free Triazole Formation as a Tool for Bioconjugation. 2007. Van Berkel. Sander S.. Dirks. A. (Ton) J.. Debets. Marjoke F.. Van Delft. Floris L.. Cornelissen. Jeroen J. L. M.. Nolte. Roeland J. M.. Roeland J. M. Nolte . Rutjes. Floris P. J. T.. ChemBioChem. 8. 13. 1504–8. 17631666. 2066/34475. free.
  3. 10.1021/ja809345d. Thiol-Selective Fluorogenic Probes for Labeling and Release. 2009. Kislukhin. Alexander A.. Hong. Vu P.. Finn. M.G.. J. Am. Chem. Soc.. 131. 9986–94. 19621956. 29. 3166955.
  4. 10.1021/ja301491h. Degradable Conjugates from Oxanorbornadiene Reagents. 2012. Kislukhin. Alexander A.. Higginson. Cody J.. Hong. Vu P.. Finn. M.G.. J. Am. Chem. Soc.. 134. 6491–7. 22455380. 14. 3432588.
  5. 10.1016/S0040-4020(01)92451-2. Site selectivity in the reactions of 1,3-dipoles with norbornadiene derivatives. 1981. Cristina. D.. De Amici. M.. De Micheli. S.. Gandolfi. R.. Tetrahedron. 37. 1349–57.